Process for the preparation of high purity pemirolast

ABSTRACT

A novel process for the purification of Pemirolast, whose potassium salt is an anti-allergic pharmaceutical product, is disclosed.

[0001] The present invention relates to a novel process for the purification of Pemirolast, whose potassium salt is an anti-allergic pharmaceutical product.

[0002] Pemirolast, or 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido-[1,2-a]-pyrimidin-4-one, has the following formula:

[0003] Several patents disclose processes for the preparation of Pemirolast Potassium.

[0004] According to all known methods, the product is firstly obtained in the acid form and then converted into the corresponding potassium salt.

[0005] As the product recovered in the acid form is very poorly soluble in conventional solvents, it always contains several by-products which can hardly be removed and only with remarkable losses in yields. The purification is usually carried out either directly on the acid form or on the corresponding potassium salt.

[0006] A novel process for the purification of Pemirolast acid form which provides high purity (>99.8% HPLC) and high yields (>85%) has now been found, and this is the object of the present invention.

[0007] The process of the invention comprises the salification of Pemirolast acid form in the presence of an amount of a primary or secondary amine ranging from 1 equivalent to 1.5 equivalents relative to Pemirolast and an amount of protic solvents such as water, C₁-C₃-alcohols or mixtures thereof ranging from 1 volume to 10 volumes relative to Pemirolast. The use of a 2:1 methanol:water mixture is preferred.

[0008] The salification is carried out at a temperature which allows to completely solubilize the salt, generally at a temperature ranging from 20 to 100° C., preferably from 40 to 80° C. When the solubilization is complete, the solution is acidified with mineral or organic acids to pH ranging from 2 to 4 in order to promote the precipitation of Pemirolast in the acid form which is then filtered, washed and dried to give a product with >99.8% HPLC purity. Suitable acids comprise formic acid, acetic acid and hydrochloric acid.

[0009] Said product can then be transformed into the corresponding potassium salt without further purification.

[0010] Primary amines for use according to the invention are C₁-C₆-alkylamines, or arylamines wherein the aryl residue can be phenyl, naphthyl or an optionally substituted aromatic heterocyclic nucleus.

[0011] Secondary amines for use according to the invention are di(C₁-C₆)alkylamines, alkylarylamines or diarylamines, wherein the alkyl or aryl residues are as defined above, or are an aliphatic and aromatic substituent and wherein the meanings for aliphatic and aromatic are those indicated above.

[0012] The invention is illustrated in greater detail in the following examples.

EXAMPLE 1

[0013] A suspension of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido-[1,2-a]-pyrimidin-4-one (68.5 g; 0.3 mols) in methanol (420 ml) and water (210 ml) heated at 50° C. is added with a 40% N-methylamine aqueous solution (30 ml, 0.35 mols) to pH=10. The solution is heated at 68-70° C., and acidified with formic acid (21 ml) to pH=3. After completion of the addition the mixture is kept at 68-70° C. for about 15 minutes and then cooled to 20-25° C. The precipitate is filtered, washed with methanol and dried under vacuum at 40° C. to give 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido-[1,2-a]-pyrimidin-4-one with >99.8% HPLC purity (63 g, 92% yield).

EXAMPLE 2

[0014] 9-Methyl-3-(1H-tetrazol-5-yl)-4H-pyrido-[1,2-a]-pyrimidin-4-one (63 g, 0.28 mols) is suspended in methanol (1000 ml). The resulting suspension is kept at 45° C. and slowly added with a 45% potassium hydroxide aqueous solution to pH 9-9.5. The suspension is stirred at 45° C. for about 15 minutes and then cooled to 20° C. The precipitate is filtered, washed with methanol and dried under vacuum at 80° C, to obtain Pemirolast Potassium (71.9 g; 0.27 mols, 96% yield) with HPLC purity >99.8%.

[0015]¹H NMR(D₂O, TMS) d (ppm): 2.02 (s, 3H); 6.83 (t, 1H); 7.22 (d, 1H); 8.18 (s, 1H); 8.47 (d, 1H). 

1. A process for the purification of Pemirolast comprising: a) salifying crude Pemirolast with a primary or secondary amine in the presence of solvents selected from water, C₁-C₃ alcohols or mixtures thereof; b) acidifying the solution obtained in a) by addition of mineral or organic acids to pH ranging from 2 to 4; c) isolating precipitated Pemirolast and optionally transforming it into the corresponding potassium salt.
 2. A process as claimed in claim 1 wherein primary amines are selected from C1-C₆ aliphatic amines or arylamines.
 3. A process as claimed in claim 1 wherein secondary amines are selected from di(C₁-C₆)alkylamines, alkylarylamines or diarylamines.
 4. A process as claimed in any one of claims 1 to 3 wherein step a) is carried out in a 2:1 methanol/water mixture.
 5. A process as claimed in any one of claims 1 to 4, wherein step b) is carried out with formic acid. 